Combining whole exome sequencing, transcriptome profiling, and T cell repertoire analysis, we investigate the spatial features of surgically-removed biopsies from multiple loci in tumor masses of 15 patients with non-small cell lung cancer (NSCLC). This revealed that the immune microenvironment has high spatial heterogeneity such that intratumoral regional variation is as large as inter-personal variation. While the local total mutational burden (TMB) is associated with local T-cell clonal expansion, local anti-tumor cytotoxicity does not directly correlate with neoantigen abundance. Together, these findings caution against that immunological signatures can be predicted solely from TMB or microenvironmental analysis from a single locus biopsy.

To define differences in tumor microenvironment (TME) immune phenotypes between right and left colorectal cancers (CRCs) and explore their therapeutic implications. Gene expression profiling and clinical characteristics of patients with CRC were retrieved from The Cancer Genome Atlas data portal. Immune cell infiltration was estimated based on single-sample gene set enrichment analysis. CRCs tissue microarrays (TMAs) containing 90 consecutive cases of surgical samples were used for validation. Expression of CD8A and VEGFA was confirmed by immunohistochemistry (IHC) analysis with TMAs, and overall survival (OS) was analyzed. Expression profiling data demonstrated that CRC immune microenvironment from right side tumor was characterized as increased infiltration of immune cells with enhanced cytotoxic function, based on higher cytotoxic activity scores (CYT) and interferon-γ signatures. Expression of VEGFA, which could be neutralized by bevacizumab, was associated with decreased levels of activated CD8+ T-cells, Th1 cells, and PRF1 expression on the right side, but not on the left side. IHC analysis of TMAs further confirmed an inverse correlation between CD8A and VEGFA expression, and revealed a favorable OS for patients with CD8AHiVEGFALo disease among right-side CRCs. For the left side, higher CD56bright natural killer cell infiltration and active 4-1BB/IFN-ɑ signaling, which could providing a favorable condition for cetuximab-mediated antibody-dependent cell-mediated cytotoxicity effect, was present in a cohort with extended OS. In the TME, features of immune phenotype sidedness were identified, providing an implication for differential responses to bevacizumab/cetuximab treatment. In addition, a new avenue for innovative experimental design and combinational immunotherapy to treat CRC patients was suggested.

High‐grade serous ovarian carcinomas (HGSOCs) were among the tumours with an unsatisfactory outcome of immune checkpoint inhibitors (ICIs). It is imperative to develop feasible biomarker for identifying responsive candidates and guiding precise immunotherapy for HGSOC patients. Here, we analysed genomic data of patients with HGSOCs to depict their immunological phenotype of tumour microenvironment (TME) and figure out the major determinants of immunogenicity. In comparison with other solid tumours, we observed the lowest levels of PD‐L1, total mutation burden (TMB) and cytolytic molecules in HGSOCs. Surprisingly, TMB is not certainly positively related to tumour immune response as it failed to predict the response to ICIs in a considerable portion of patients in previous clinical trials. By a machine learning approach in search of biomarkers for immunotherapy implications for HGSOCs, we identified the ten most dominant factors determining the immunogenicity of HGSOCs. Interestingly, we found that BRCA1 mutated tumours presented a potent immunogenic phenotype, independent of TMB, meeting the criteria of both our dominant factors and the determinants of immunogenicity established before. Our findings provide evidence that BRCA1‐mutation may be served as a predictive biomarker in guiding ICI therapies for the patients with HGSOCs.

The efficacy of cancer immunotherapy is dictated by CD8+ T cell infiltration and the nature of the tumor microenvironment (TME). By inflaming the TME to favor CD8+ T cell immunity, radiation is now widely considered as a neoadjuvant for immunomodulation. Here, we observed that local irradiation enhances the infiltration of intratumoral eosinophils, and depletion of eosinophil dampens CD8+ T cell infiltration and diminishes the anti-tumor effectiveness of radiation. Retrospectively, we identified a strong correlation between eosinophilia and survival benefit in radiation-treated cancer patients. Experimentally, we further show that radiation enhances the intratumoral infiltration of adoptive transferred T cells therapy, bolstering eosinophils by intravenous interleukin-5 administration promotes the efficacy of radiation-induced abscopal effect. Together, these results suggest that eosinophil mobilization can be considered as a mechanistically relevant biomarker for predicting the effectiveness of pre-immunotherapy radiation, as well as a new strategy to enhance T cell-mediated immunotherapy against cancers.

BackgroundA suppressive immune microenvironment and pathological angiogenesis are hallmarks of gastric cancer. Theoretically, immune checkpoint inhibitors (ICIs) stimulate pre-primed neoantigen-specific T cells, and antiangiogenic agents then facilitate their infiltration into the tumor niche by promoting vascular normalization. Currently, the interconnections of these two phenotypes and their relevance to the tumor microenvironment (TME) have not been fully characterized in gastric cancer.Materials and methodsTranscriptome profiling data retrieved from The Cancer Genome Atlas (TCGA) database were used to deconvolute the feature of TME for gastric cancer (N = 375). Machine learning, correlation, and prognosis analysis were applied to elucidate the correlations between angiogenesis, cytotoxic T lymphocyte infiltration, and patient survival.ResultsSubstantial heterogeneous infiltration of immune cell populations among cases was observed. Furthermore, among targetable pathways, angiogenesis was identified as the dominant factor in discriminating different infiltration statuses. Most importantly, the angiogenesis pathway was negatively correlated with the amount of activated CD8+ T cells only for patients with a higher infiltration, and the concomitance of low angiogenesis signaling and highly activated CD8+ T-cell infiltration was associated with a significant survival benefit.ConclusionOur findings demonstrated a negative correlation between angiogenesis signaling and cytotoxic function in gastric cancer patients with a highly infiltrated immune niche. These data provided a rationale for potential combination strategy and further clinical investigations of ICIs plus antiangiogenesis agents for patients with gastric cancer with an inflamed TME.

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Background: Previous studies indicated that type 2 diabetes mellitus (T2DM) is related to an increased lung cancer risk, but its role in the prognosis of NSCLC remains conflicting. This study investigated the impact of blood glucose control on the outcomes in NSCLC patients with T2DM treated with platinum-based doublets. Methods: Clinicopathological and survival data from 191 T2DM patients with advanced NSCLC, who received platinum-based chemotherapy, were retrospectively analyzed. Based on the blood glucose conditions during chemotherapy, patients were classified into poor (n = 84) and good control (n = 107) groups. Progression-free survival (PFS) was assessed using the Kaplan-Meier method. Results: The median PFS among patients with good glycemic control [197.0 (95% CI: 136.3-257.7) days] was longer than that among those with poor control [132.0 (95% CI: 112.5-151.5) days] (P = .0003). Further subgroup analysis of lung squamous carcinoma and adenocarcinoma patients showed that the median PFS of the good control group was also significantly longer than that of the poor control group [179.0 (95% CI: 78.4-279.6) days vs 125.0 (95% CI: 110.9-139.1) days, P = .0014;197.0 (95% CI: 124.3-269.7) days vs 154.0 (95% CI: 129.9-178.1) days, P = .0359; respectively]. The incidence rates of side effects were similar among patients with good glycemic control and those with poor glycemic control (all P > .05). Conclusions: Satisfactory glycemic control during platinum-based chemotherapy might provide a survival benefit to T2DM patients with NSCLC. Further studies are warranted to confirm our findings. K E Y W O R D Sglycemic control level, non-small cell lung cancer, platinum-based chemotherapy, progression-free survival, type 2 diabetes mellitus | 903 ZENG Et al.

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